6-phenoxymethylpteridines



Patented Oct. 20, 1953 David 'Ii-Weisblat and Barney J. Mag'erlein, Kala-- mazoo; Mich:, I assignors. to The Upjohn Company, Kalamazoo,-Mich., a'corporation of Michigan No Drawing. Application February 24, 1951, Serial No. 212,668-

11 Claims. (01160-2515) This invention relates to fi-phen'oxymethylpteridines, and to a method for theirpreparation. Among the 6-phenoxymethylpteridines' of this invention are those represented by the halogen and" alkyl. and Y is a member of the group consisting of hydrogen nitro, amino,

halogen, alkyl, hydroxyhalkoxyl; sulfonic acid, carboxylic acid,.and esters 1 and amides? of the sulfonic acid and carboxylic acid groups.

- Theipteridines of this invention areyellow to brown solids; soluble in aqueous' alkalies: and acids, sparingly 'soluble in" water and relatively insoluble in. most. common. organici solvents.

Theychar and decompose?without deflnite melting when heated 1 above: 300 degrees centigrade and are: best characterized by their; ultraviolet absorptionspectra; They are useful as folic acid antagonists, difiering from many other products which are folic acid: antagonists- 2 in that: their action is reversed, usually quantitatively, by the administration of a further: quantity of' folio acid.

'Theyfiare also useful as-anti viral agenta and as enzyme inhibitors. The preparationof 6 phenoxymethylpteridines is accomplished by contacting insolution a 4;5diaminopyrimidine and a 3: phenoxy2 ketcpropylacetal; heating the solution to complete the reaction, coo1ing andrecovering ithe-*6-phenoxymethylpteridine thus obtained. lfheprepaof the: following diagram:

' II A 4,'5-diamino-pyrimidine A 3-phenoxy-2-ketopropyl'acetal I A 6-phenoxymethyl pteridine wherein Rrepresents a lower alkyl radicaland Y and Z have the valuesalready'g-ivene .rationi ofthesepteridines*is illustratedrby means 40 .Aapreferred' method for carrying outthe synthesis of. 6-phenoxymethylpteridines comprises dissolving the 3-phenoxy-2 -ketopropylacetal in glacial acetic acid and adding this solution to a water solution of the 4;5"-diaminopyrimidine. The solution of the 4,5'-diaminopyrimidine is preferably prepared, just prior to use, by the neutralization of a water solution of an acid addition salt of the 4,5-diaminopyrimidine, suchas-the dihydrochloride or sulfate, by means of an alkali metal salt' of a weak acid, such as sodium acetate, sodium carbonate, sodium bicarbonate and the like with sodium acetate being preferred.

The preparation of the free pyrimidine 'bases in this manner'isdesirable because-of? their iiistability and lack of keeping qualityin storage,

the acid additionsalts being much sup'eririr in this respect. It is also" advantageous to: carry out the condensation iri'the absence'of light and 'in" a neutral, 'non oxidiz'i'ng atmosphere such' as is provided by nitrogen, methane, ethane and the like. After mixing the reagents' theii-miicture is heated for about thirty minutes to two hours to complete the reaction after which the mixture is cooled and the G-phenoxymethylpteridine which separates is collected washed and dried. It can be purified further if desired by dissolving 1 it in acid orralkali: followed by.-' dilution or neutralization and collecting the pteri'dine' which precipitates:

The preparation of the required 3'+phenox'y2- ketopropylacetals can be accomplished by oxidizing the? corresponding 3=-phenoxy=2 hydfoxypropylacetal' as illustratedibel'ow OH Y oxidation Ro ,o11-r -oHT-o' o c r Y wherein R; and Y have: thelvalues previously assigned. This oxidation can be accomplished by those known methods for: oxidizing secondary alcohols to ketones which are conducted under such mild reaction conditions-that the acetal will :not be hydrolyzed to the'aldehydea When the oxidation is carried out under acid condiwhen Y is a carboxyl or a sulfonic acid group, I

preparation of the keto-acetal is preferably accomplished by hydrolysis of the corresponding sulfonic or carboxylic acid ester as it is difiicult, if not impossible, to obtain the hydroxyacetal required for the oxidation step. When Y represents NH: it is preferred that the keto acetal be obtained by reduction of the compound wherein Y represents N02 as amino-benzenes are subject to attack by strong oxidizing agents.

Those hydroxyacetals wherein Y is not a free carboxylic acid or sulfonic acid can be obtained by the condensation of a 1,2-epoxy propionaldehyde dialkylacetal with a hydroxy benzene compound according to the equation:

VI V

wherein R has the value previously assigned and -Y1 is a member of the group consisting of hydrogen, amino, halogen, hydroxyl, alkoxyl, alkyl, carboxylic acid esters, carboxylic acid amides, sulfonic acid esters, and sulfonic acid amides, differing from Y in that carboxylic acids and sulfonic acids are excluded for reasons previously mentioned.

The compounds wherein R. has the values previously assigned can be prepared from the corresponding acrolein acetals, CH2=CH-CH(OR)2, by the addition of hypochlorous acid (H001) to give a 2-hydroxy-3-chloro acetal,

C1-CH2-CH( OH) OR) 2 followed by cyclization using alkali to give the desired oxido-acetals according to methods described in the art. Dialkylacetals of 1,2-oxidopropanal which can be used in the process include the dimethyl, diethyl, di-n-propyl, di-isopropyl, dibutyl, diamyl and other dialkyl acetals. As a matter of convenience and availability dialkylacetals wherein the alkyl radicals each contain less than 8 carbon atoms are preferred, although others can be used if desired. It is apparent that the nature of the alkyl groups in the 3,3-dialkyl-2-hydroxy propyl and in the 3,3-dialkyl-2-keto-propyl radicals of the intermediate Compounds II and IV are determined by the particular 1,2-oxidopropanyl dialkylacetal used in the first step of the process.

The following examples which illustrate this invention are subject to variations readily appreciated by those skilled in the art to which this invention pertains.

PREPARATION 1.ETHYL-P(2-HYDBOXY-3,3DIETHOXY- PROPOXY) BENZOATE A clear solution of 292 grams of 2,3-oxidopropanyl diethylacetal and 332 grams of ethylpara-hydroxybenzoate was prepared by melting the ethyl para-hydroxybenzoate at degrees centigrade adding the oxidopropanyl acetal and stirring the solution for about five minutes. To the clear solution thus prepared 0.5 milliliter of pyridine was added and the temperature of the reaction mixture raised gradually to about 158 degrees centigrade over a period of about 15 minutes. An additional 0.5 milliliter of pyridine was added whereupon the reaction temperature rose rapidly to 175 degrees centigrade. The reaction temperature was then reduced to about degrees centigrade by external cooling and was maintained at 155-160 degrees centigrade for an additional 90 minutes. The mixture was then cooled to room temperature and dissolved in 500 milliliters of ether. The organic solution was washed twice with 500-mi1liliter portions of water and twice with 250-milliliter portions of 3 percent sodium hydroxide solution and then twice more with water. The organic layer was dried by shaking it with 250 milliliters of saturated sodium chloride solution separating the organic layer and filtering it through a bed of anhydrous sodium sulfate. The ether was removed and the residual oil distilled under reduced pressure. There was obtained 460 grams of a yellow oil distilling between 171 and 175 degrees centigrade at a pressure of 0.6 millimeter of mercury which, after crystallization from commercial hexane, gave ethyl-p-(2-hydroxy-3,3-diethoxypropoxy) -benzoate as a white crystalline solid melting at 30-335 degrees centigrade.

In a like manner from 2,3-oxidopropanyl di butyl acetal and butyl-p-hydroxybenzoate, butyl (p 2 hydroxy 3,3 dibutoxypropoxy) benzoate is obtained. Likewise from 2,3-oxidopropanyl diethyl acetal and p-amino-phenol, para (2 hydroxy 3,3 diethoxypropoxy) aminobenzene is obtained; from 2,3-oxidopropanyl dibutyl acetal and ortho chlorophenol, ortho-(2-hydroxy-3,3-dibutoxypropoxy) chlorobenzene is obtained; from 2,3-oxido-propanyl dipropylacetal and p-bromobenzene, para-(Z-hydroxy-3,S-dipropoxypropoxy) bromobenzene is obtained; from 2,3-oxidopropanyldiethy1 acetal and p-nitrophenol, para (2 hydroxy 3,3 diethoxy-propoxy) -nitrobenzene is obtained; from p-ethylphenol and 2,3-oxidopropanyldiethylacetal, para-(Z-hydroxy 3,3 diethoxypropoxy) ethyl benzene is obtained, from hydroquinone monoethyl ether and 2,3-oxidopropanyl diethylacetal, para (2-hydroxy3,3-diethoxypropoxy)- ethoxybenzene is obtained; from p-hydroxybernamide and 2,3-oxidopropanyldibuty1 acetal, p-(2-hydroxy-3,3-dibutoxypropoxy) benzamide is obtained; from ethyl-p-hydroxybenzene sulfonate and 2,3-oxido-propanyl diethylacetal, ethyl p (Z-hydroxy 3,3 diethoxypropoxy) benzene sulfonate is obtained.

PREPARATION Elk-ETHYL-P- 25KEro 3,3'-nLETHoxYe Y rxoroxxq'nnnzoA-rnr de solution. of, 237.54 gramsv of sodium dichromate dihydrate dissolved in a mixture of 12170 milliliters of water andv36l. milliliters of concentrated sulfuric acidiwascooled to about 5.de,- grees centigrade. and .7 added to a solution..0f."1 6 3 grams of ethylen-(2ehydroxy-3,Bdiethoxypro: poxy)benzoate dissolved in two, liters of: chlorobenzene ate-such a rate thatithe temperature of the reaction, mixture withthe help of 'jexternal; cooling was maintained between about. 5 Ia'ndfabout 8 degrees centigradeduring the addition. At the end of about an hour, one liter of" benzene was addedto the. reaction mixture and, the organic layer. separated. The aqueous layerwas extracted twice with 500.-milliliter portionsofpbenzene. The combined benzene layers were washed once with, 1500 millilitersof water andtwice with l500-milliliter portions of Super.- jcent' saturated, sodium chloride solution. The organic layer was dried by shaking it with saturated sodium chloride solution, separating the organic'layer stirring it with anhydrous sodium sulfate, and filtering; The solvent was removed and'theresidual oil distilled under reduced pressure." There was thus obtained 123 grams of ethyl p- (2'- keto 3,3 diethoxypropoxy-)benzoate as'gayellow oil, N =1;5058.

In alike manner, the oxidation ofjbutyl-p- (Z-hydroxy-Zi-B-dibutoxypropoxy)benzoate giwes butyl p (2 keto 3,3 dibutoxypropoxy)ben- -zoate; the oxidation of p-(2-hydroxy-3,3-diethoxypropoxy)nitrobenzene gives 3;3-diethoxypropoxy) nitrobenzene which on reduction gives p-(2 keto-3,3-diethoxypropoxy) aminohenzene; theoxidation of ortho-(Z-hydroxy-3,3-dibutoxypropoxy)chloro benzene gives ortho, (2 keto 3,3 dzibutoxyprop oxyh chlorobenzene; the oxidation of" p-(Z-hydroxy 3j3 dipropoxy-propoxy) -bromobenzen e' gives. p; (Z- keto. 3,3' dipropoxypropoxy) bromo- ,benzene; the oxidation of p -(2-hydroxy -3;3-diethoxypro'pp y) ethylbenzene gives p-(Z-keto- 3,3j-diethoxypropoxy) ethyl benzene; the oxida tion of p -(2-hydroxy-3,3-diethoxy propoxy) ethoxy benzene. gives p -(Z-keto-313-diethoxypropoxy) ethoxybenzene; the oxidation OffP -(Z- hydroxy 3i,3'-dibutoXYPI p oXy) benzamide, gives D- 2-keto-3,3-dib 1 Q n opoxy) benzam de and the oxidati n o ethy enz hy roxyrmrdi fethoxypr p enzene sulfonate ,gives, ethy -ne (z=ket 3;3edieth xypropoxy) benzen sulf nat The saponification of. ethy1en- 2;-ket0w3;3.-diethoxy propoxybenzoate), followed by, careful neutralization gives 11,- z-ketoawrdi hoxypro- R xy e zoicia ld.

Example 1..-.vEthyZ4 (2'ami1vo-4ehydroxy-6- pyrimid01- [4,'5eb] .-.pyralzyZ-) -meth;o:nyvl cosy}- beneoate also called 2-lz-mino -4-hydroxyrd-(pcarbethowyphenoxy) -methyl"pter1ldine A solution...of 0.8 gram of, ethyl-p- (2':l eto:3,3

diethoxypropoxy) benzoate; 14.8 milliliters, of

glacialaceticacid was addedto a mixture of 0.42

ramof, sodium acetate and. 0.55,. gram of. 2,4,5,-

triaminor6rhydroxyl pyrimidine dihydrochloride.

The mixture was stirred for I thirty: minutes; at

room temperature in; the darkv under: an atmosphere-of nitrogen-then heatedto 118-120 degrees and stirred for-an additionaltwenty minutes; The mixture was cooled,to,about;zerodegrees .centigrade and'the, dark colored precipitate which-had separated. was collected. After washing twice p-(2-ketowith: water and: once withv acetone and; drying therewas. obtained 0.58 gram -oi-2'iam inoe4;-;hy:- droxy- 6- (prcarbethoxyphenyl) -methylpteridine:p

The condensation, in: a-like manner'using' glae cial aceticzacid. as asolvent; of ;butyl-p. (2.+,keto1- afi-vdibutoxypropoxy)benzoate and: 2.,4;5=triami= nQ-G-hydr Xypyrimidine gives 2:-. amino-4:1- hydroxy-S-(p-carbobutoxyphenoxy) methyl uteri: dine. Similarly the condensation ofgethylepe (21'- KGtOrIiBdiGthOXYPIODOXY)11611203478 and. 2;4;5.,6- tetraaminopyrimidine gives- 2,4-diamino:-6i-1(p= carbethoxyphenoxy) -methylpteridine;- the: condensation, of; ethylepe (2-=keto 3,3 diethoxyproa- 'poxy) benzoate and 4 5',6i-triaminopyrimidine gives 4': amino-6- (p carbethoxyphenoxy) methylpterie dine; the condensationof ethylp- (2=l eto.-3,3:- diethoxypropoxy) benzoate and 4,5 ;6-triamino;-.2- methyl thiol: pyrimidine gives 2-methylthio14- amino 6 -(p carbethoxyphenoxy) -methylpteri'.- dine; the condensation of Lethyl-per2rketo-3;3;edi+ etho'xy propoxy) benzoate and"4,5,6-triamin0-=2!- thiolpyrimidine gives 2-thiole4-aminoe6r-( pecar bethoxyphenoxy) -methyl pteridine; the condemsation of ethyl-p- (2-keto-3,3-dieth0xy-propoxy) benzoate and 4,5,6'-:triamino.-z-methylpyrimidine gives 2-methyl '4 amino-6 (p-carbethoxyphevnoxy) r-methylpteridinegthe condensation of eth+ yl-pe- (2-keto-3,3 diethoxypropoxy) benzoate and 4,5i-diaminopyrimidine gives 63 (plcarbethoxyphenoxy) -methylpteridine;; the condensation of: 2'- methyl 4,5 diamino-fi-hydroxypyrimidine andethyl -v (2, keto,-. 3,3 diethoxypropoxy).benzoate gives 2-methyl+4,,-hydroxy6- (pi carbethoxyphenoxy) -methy1-pteridine; the condensation of 4,5- diamino-2 chloropyrimidine and ethyl-p- (2+keto- 3',3"-diethoxypropoxy) benzoategive's- 2'-chlo'ro- 6- (p-carbethoxyphenoxy) methylpteridine thecondensation of 2,6-dihydroxy-4,5-diamino-pteridine and ethyl-p -(2*keto-3,3-diethoxypropoxy) benzoate gives- 2,4-dihydroxy-6-(p carbethoxy-phnoxy)methylpteridine;- the condensation of Z-ethylthiol-4,5-diamino 6 hydroxypyrimidine and ethyl-p-(Z-ketc 3, 3 diethoxypropoxy)benzoate gives 2-ethylthioli-hydroxy-fi (p carbethoxyphenoxy)methyl pteridine; the condensation of 2,6-.dimethyl*4,5-diaminopyrimidine and ethyl-p- (-2-keto-3;3'-diethoxypropoxy)benzoate gives 2,4- dimethyl-G (-p-carbethoxyphenoxy) methylpteridine; the condensation of2-chloro4;5-diaminoethoxypropoxy-M benzoate gives 2chloro-4'-ethy1 6'- (p carbethoxyphenoxy)methy1pteridine;- the d s pn o ,2rthiol4,5;diaminor6- yd o pyrimidine and ethylene (2 keto-3,3-diethoxypropoxy) benzoate givesz. 2-thiol-4-hydroxy-6- (pcarbethoxyphenoxy)- methylpteridine; the condensation of 45 diamino 6 methylpyrimidine and ethyl-p-(2-keto-3;3'-diethoxypropoxy)benzoate gives 4-niethyl'-6-(pcarbethoxyphenoxy)- methylpteridinmthe-r condensation of; 2;4,5+triaminopyridineaand ethyl p-. (2-keto-3,3,-'- GiGtHOXYzpropoxyphenoxy) methylpteridine; gives 2; amino:- 6, (pcarbethoxyphenoxy) methylpterid-ine; the condensation of; 2,4,5: triamino 6 chloropy rimidine and ethylp.--(2j-l eto -w 3;3 diethoxypropox-y)b enzoate. gives 2 amino- 4- chloro:-6'-: (p-carbethoxyphenoxy)methylpteridine and the condensation of 2;4;5triamino-G-methylpyrimidine gives Z-amino--methyl-S (pecarbethoxyphenoxy) methylpteridine. Likewise the condensation of p-2-keto-3,3-diethoxypropoxybenzoic acid with-2,4,5-triamino-6- hydroxypyrimidine inglacial acetic acid gives 2- aminoll-hydroxy-S-(p-carboXyphehoxy) methylpteridine and the condensation of 2,4,5-triamino- 6,-hy'droxy pyrimidine and p (2 keto 3,3 diethoxypropoxy)-benzene sulfonic acid gives 2- amino-4-hydroxy-6-(p-oxybenzenesulfonic acid) methylpteridine although the preferred method of preparing these compounds having free carboXy and sulfonic acid groups is by the hydrolysis of esters such as are described above according to the procedure given in Example 2.

Likewise the condensation of 4,5,6-triamino-pyriinidine and p-(2-keto-3,3-diethoxypropoxy)nitro benzene gives 4-amino-6-(p-nitrophenoxy) methylpteridine; the condensation of p-(2-keto- 3,3- diethoxypropoxy)amino benzene with 2- methylthiol 4,5;6 triaminopyrimidine gives 2- methylthiol 4 amino 6 (p aminophenoxy)- methylpteridine; the condensation of 2-thiol- 4,5,6-triaminopyrimidine and ortho-(2-keto-3,3- dibutoxypropoxy)chloro-benzene gives 2-thiol-4- amino 6 (ortho chlorophenoxy) methylpteridine; the condensation of 2-methyl-4,5,6-tri amino pyrimidine and p-(2-keto-3,3-dipropoxylbromobenzene gives 2-methyl-4-amino-6-(p-bromophenoxy) methylpteridine; the condensation of 2,4,5,G-tetraaminopyrimidine and p-(2-keto- -3,3-diethoxypropoxy)ethyl benzene gives 2,4-diamino-6- (p-ethylphenoxy) methylpteridine; the condensation of 2,6-dihydroXy-4,5-diamin-pyrimidine with p- (2-keto-3,3-dibutoXy-propoxy) benzamide gives 2,4-dihydroxy-6-(p-carbamidophenoxy) methylpteridine.

Example 2. 2 amino-4-hydrom -6- (p-carboxyphenomy) mcthylpterz'dine The 2-amino-4-hydroxy-6-(p-carbethoxyphenoxy)-methylpteridine from Example 1 was dissolved in ten percent sodium hydroxide solution and after standing for one hour at room temperature, the pH was adjusted to 3.0. There was thus obtained 0.49 gram of crude pteridine which was further purified by solution in 100 milliliters of one normal sodium hydroxide and dilution to 500 milliliters. To this solution was added calcium hydroxide solution and the mixture stirred at room temperature in the dark for 90 minutes, filtered, the filtrate heated to boiling, filtered, reheated to boiling and the pH adjusted to 3.0 with concentrated hydrochloric acid. A yellow precipitate separated which was collected and dried under vacuum to give 2-amino-4-hydroxy-6-(pcarboxyphenoxy)methylpteridine whose ultraviolet absorption spectra gave the following data:

ned...

thiol-4-amino- 6 (p carbethoxyphenoxy)methylpterdine gives 2 thiol 4 amino 6 (pcarboxyphenoxy)methylpteridine; 2- methyl 4 amino 6 (p carbethoxyphenoxy)methylptericline gives 2 methyl 4 amino 6 (pcarboxyphenoxy)methylpteridine; 6 (p carbethoxyphenoxy)methylpteridine gives 6-(pcarboxyphenoxy)methylpteridine; 2 methyl-4- hydroxy- 6 (p carbethoxyphenoxy)methylpter idine gives 2-methyl-4-hydroxy-(p-carboxyphenoxy)methylpteridine; 2-chloro 6- (p carbethoxyphenoxy) methylpteridine gives 2-chloro-6-(pcarboxyphenoxy) methylpteridine; 2,4-dihydroxy- 6- (p carbethoxyphenoxy)methylpteridine gives 2,4 dihydroxy 6 (p carboxyphenoxy)methyl pteridine; Z-ethylthiol 4- amino-G- (p carbethoxypropoxy)methylpteridine gives 2-ethyl-thiol- 4-amino 6 (p carboxyphenoxy) methylpteridine; 2,4 dimethyl-G- (p carbethoxyphenoxy methylpteridine gives 2,4 dimethyl-G- (p carboxyphenoxy) methylpteridine; 2-ch1oro-4-ethyl- 6- (p oarbethoxyphenoxy)methylpteridine gives 2- ch1oro-4-ethyl-6- (p-carboxyphenoxy) methylpteridine; 2-thiol-4-hydroxy-6- (p carbethoxyphenoxylmethylpteridine gives 2 thiol 4 hydroxy-6- (p-carboxyphenoxy) methylpteridine; 4- methyl 6 (p carbethoxyphenoxy)methylpteridine gives 4-methyl-6- (p-carboxyphenoxy)methylpteridine; 2-amino-6- (p-carbethoxyphenoxy) methylpteridine gives 2-a1hino-6-(p-carboxyphenoxy)methylpteridine; 2 amino-4-chloro-6-(pcarbethoxyphenoxy) methylpteridine gives 2-amino-4-chloro-6- (p carboxyphenoxy)methylpteridine; and Z-amino 4 methyl-6- (p-carbethoxyphenoxy methylpteridine gives 2-amino-4-methyl-S- (p-carboxyphenoxy) methylpteridine.

PREPARATION 3.--DIETHYL P-ACETOXYBENZOYL-L- GLUTAl-IATE Fifty inilliliters of toluene was distilled from a solution of 18 grams of p-acetoxybenzoic acid in 300 milliliters of toluene to remove any water from the solution. The solution was then cooled to about 45 degrees centigrade and 2 drops of pyridine was added followed by 54 milliliters of thionyl chloride in two equal portions. After about one-half hour the temperature of the reaction mixture had risen to 58 degrees centigrade and a clear solution formed. The mixture was maintained at 50 degrees centigrade with stirring for an additional four hours, whereupon the excess thionyl chloride and the toluene were removed by distillation under reduced pressure. The residual yellow p-acetoxybenzoyl chloride was dissolved in milliliters of ethylene dichloride and to it was added solution of 24 grams of diethyl-L-glutamate hydrochloride in 50 milliliters of ethylene dichloride. The resulting solution was stirred and cooled to 15 degrees centigrade and to it was added 22.2 grams of triethyl amine at such a rate that the temperature of the cooled reaction mixture was kept below about 20 degree centigrade. After the addition of the triethyl amine was complete and the exothermic reaction had subsided, the solution was stirred for an additional hour at room temperature. The reaction product was recovered by washing the solution twice with 50-milliliter portions of water, once with 50 milliliters of 2-normal HCl, twice with 50-milliliter portions of saturated sodium bicarbonate solution and finally with two 50- milliliter portions of water, drying the organic layer, removing the solvent and distilling the residue under reduced pressure. There was thus obtained 33.1 grams of diethyl p-acetoxybenzoyl- Ina similar manner ii-acetoiiyb'enzene' sulfonic a did and"dibutylii iglutafiiat "gives "dibutyl-p f acetoiiybenz'ene siilfoi'iyl-L glutafnic' acid emirates Ten grams diethyl p acetdxybenzoyl li 'glu tainate from Preparation 3 was dissolved in 200 milliliters of absolute ethanol and to the solution was added 3.0 grains of p-to'luen'esulfonic acid nionohydrate. The solution was heated under gentle reflux for about 40 minutes and their ethanol was distilled slowly from it for about five: hours. At this time the'remaining ethanol was removed rapidly and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed well with water and sodiurn bicarhgnate solution, dried and cbii'ce'htrf'diuncl e There thus Qlpt'aii ned '8 2 grams of diethyl- -hydro'xyhnioylm glutaifiate' melting at 79 to 85 degrees Centigrade a-] 14.4 degrees.

In asimilar manner the selective hydrolysis of diethyl p acetoxyb'enzene sulfonyl L glu-' tamate gives diethyl p hydroxybenzenesulfonyr-fig lutarnate.

merri- To 3.23 grams of diethyl P-hYdTOXYiJBH ZOYi'TiI-I': glutamate, heated to above its melting point; 1-.'75 grams of 2,3oxidopropanyl 'diethylaceta-Larrd three drops of pyridine were added. The temperature of the mixture was raised first, to about 130-135 degrees centigrade and then gradually to 143 degrees centig-rad' where it measures for about two hours and then' cooled to room temperature. The diethyl-p (-2- 'hydroky-3;3 di ethoxypropoxy)benzoyl L glutamate thus 01o tain'ed hadan' index of refraction N' lfiom;

In a; like manner dibuty1=p hydroxybenzene sul-fonyl-L glutarirate and 2 ,3-'ox-i'dopropanyldi-" butylaoetal when heated together in the presence of pyridine give 'di'butyl-p-(2-hydroxy-3;3 di butoxypropoxy) benzenesulfonyl-Lglutamate;

Asoluti'onof the diethyl p-(2-'hydroxy-3,3-jdithox'ypropoxy) benzoyl L-glutamat'e from Prep ara'tion 5? in 38- milliliters of chlorobenzene' was, added with stirring toasolution of 5 .;3 grams oi sodium dichromateldihydrate and 6.9 milliliters of concentratedsulfuric acid whilevv maintaining the reaction temperature between about two anc l bou x d e ntig d -during??? dd n. or the glutamat'e and for an additional two hours. e r hl z nel ased ii s by ihw nl of benzene and the water layer separated. watei iayerwas eigtiacted; txfiic'withBU-igilli 'e'r portions of benzene the Benzene extracts b combined. The co med lienliii eiitr'ajc'ts' washed ua're with water dii'e y h with saturated sodiur fii chloride soluti I 1) dried by filtering mister; Seams; sulfate. The solvent was rem vedji nderjedued pressure'and there was obta ned 2.7 g ramsoii diins/"1 p- 2 kefid-s,s-diethoxyiiiobiiyip figo -nglutafiiateias a y n'gwan navmg'a'h' index of rerfactio'fi N' '=1.5o48:

1 The 2.7 "grams of "diethyl .-.p .(2 keto -..-3,3 diethoxypropoxy) benzoyl Ii e glutamateufroni Preparation 6 dissolved in 48, millilitersgglaciail acetic aid was added to 'amixture of l.38.grams of sodium acetate and 1.8 .grams of 2,4,5-triaihino' L 6' hydroxypyrimjidine dihydrochloride The mixture was stirred undernitrogen in the dark for thirty fninutes: at room temperature. and I then heated to about -110 degreescentigrade for an" hour.v The reactionumixture was cooled and the dark precipitate which; had separated was collected; washed threeht imes with water; driedandthen washed with ethylacetate, There was thus obtained ,0;.2 gram. orgieriiyl-N-i ini- [(,2-'amino -V 4 :hydroxy 6M pyrimido f ,5" b] pyrazyl) methyl-1 oxylwbenz yn, v iglutamate (alsol called ZramiI Q -QYQIQXXTQ [Dara N (-diethrl @1- lutarat :a h m dqph yl-methylpt ridmeeLwhcse;.ultrayiqlete sorption curve showed the following properties.

I l sation of 4,5,6-triamino-2-methylmercaptopyrimidine and diethyl p (2-keto 3,3 diethoxypropoxy) benzoyl L glutamate gives 2- methylmercapto 4 amino 6 [para N (diethyl a glutarate) carbamidophenoxylmethylpteridine; the condensation of 4,5,6-triamino-2- thiopyrimidine and diethyl p-(2-keto-3,3-diethoxypropoxy)benzoyl L glutamate gives 2- thio 4 amino 6 [para N (diethyl aglutarate) carbamidophenoxylmethylpteridine; the condensation of 4,5,6 triamino 2 methylpyrimidine and diethyl p (2 keto 3,3 diethoxypropoxy) benzoyl L glutamate gives 2 methyl 4 amino 6 [para N (diethyla. glutarate)carbamidophenoxy] methylpteridine; the condensation of 2,4,5,6 tetraaminopyrimidine and diethyl p (2 keto 3,3 diethoxypropoxy) benzoyl L glutamate gives 2,4 diamino 6 [para N (diethyl a glutarate) carbamidophenoxy] methylpteridine the condensation of 4,5 diaminopyrimidine and diethyl p- (2 keto 3,3 diethoxypropoxy) benzoyl L- glutamate gives 6 [para N (diethyl a. glutarate)carbamidophenoxy] methylpteridine; the condensation of 4,5 diamino 6 hydroxy- 2 methylpyrimidine and diethyl p (2 keto- 3,3 diethoxypropoxy benzoyl L glutamate gives 2 methyl 4 hydroxy 6 [para N (diethyl a glutarate)carbamidophenoxyJmethyk pteridine; the condensation of 4,5 diamino 2- chloropyrimidine and diethyl p (2 keto 3,3- diethoxypropoxy) benzoyl L glutamate gives 2- chloro 6 [para N (diethyl a, glutarate) carbamidophenoxy] methylpteridine the condensation of 4,5 diamino 2,6 dihydroxy pyrimidine and diethyl p (2 keto 3,3 diethoxypropoxy) benzoyl L glutamate gives 2,4 dihydroxy 6 [para N (diethyl a. glutarate) carbamidophenoxy]methylpteridine; the condensation of 4,5 diamino 2 ethylmercapto 6- hydroxypyrimidine and diethyl p (2 keto 3,3- diethoxypropoxy benzoyl L glutamate gives 2 ethylmercapto 4 hydroxy 6 [para N- (diethyl a glutarate) carbamidophenoxylmethylpteridine; the condensation of 4,5 diamino- 2,6 dimethylpyrimidine and diethyl p (2- keto 3,3 diethoxypropoxy) benzoyl L glutamate gives 2,4 dimethyl 7 6 [para N(diethyl a glutarate) carhamidophenoxylmethylpteridine; the condensation of 4,5 diamino- 2 chloro 6 ethylpyflmidine and diethyl p (2 keto 3,3 diethoxypropoxy)benzoyl L glutamate gives 2 chloro 4 ethyl- 6 [para N (diethyl a. glutarate) carbamidophenoxy] methylpteridine; the condensation of 4,5 diamino 2 thio 6 hydroxpyrimidine and diethyl p (2 keto 3,3 diethoxypropoxy) benzoyl L glutamate gives 2 thio 4 hydroxy 6 [para N (diethyl u. glutarate) carbamidophenoxy] methylpteridine; the condensation of 4,5 diamino 6 methylpyrimidine and diethyl p (2 keto 3,3 diethoxypropoxy) benzoyl L glutamate gives 4 methyl 6 [para- N (diethyl u. glutarate) carbamidophenoxylmethylpteridine; the condensation of 2,4,5- triaminopyrimidine and diethyl p (2 keto 3,3- diethoxypropoxy) benzoyl L glutamate gives 2 amino 6 [para N (diethyl a glutarate) carbamidophenoxy] methylpteridine; the condensation of 2,4,5 triamino 6 chloropyrimidine and diethyl p (2 keto 3,3 diethoxypropoxy) benzoyl L glutamate gives 2- amino 4 chloro 6 [para N (diethyl aglutarate) carbamidophenoxy} methylpteridine; and the condensation of 2,4,5 triamino 6- methylpyrimidine and diethyl p (2 keto -'3,3'- diethoxypropoxy) benzoyl L glutamate gives 2 amino -4 methyl 6 [para N (diethyla glutarate) carbamidophenoxy]methylpteridine.

In a like manner the condensation of 4,5,6 triamino 2 thio pyrimidine and diethyl p (2- keto 3,3 dibutoxypropoxy) benzenesulfonyl L- glutamate gives 2 thio 4 amino 6 [para- N (diethyl a. glutarate) sulfonamidophenoxy] methylpteridine; the condensation of 2,4,25,6- tetraaminopyrimidine and diethyl p (2 keto 3,3 dibutoxypropoxy)benzenesulfonyl L glutamate gives 2,4 diamino 6 [para N (diethyl a glutarate) sulfonamidophenoxylmethylpteridine; and the condensation of 4,5- diamino 2,6 dihydroxypyrimidine and diethylp (2 keto 3,3 dibutoxypropoxy)benzenesulfonyl L glutamate gives 2,4 dihydroxy 6- [para N (diethyl a glutarate)sulfonamidophenoxyl methylpteridine.

Example 4. N [4 [2 amino-4-hydroacy-6- pyrimido [4,5-bl pyrazyl methyl] -oacy}benzoyll L-glutamie acidwxopterin-G) A solution of 0.5 gram of the pteridine, from Example 3, was dissolved in milliliters of 0.1 N sodium hydroxide and diluted with 2 liters of water. To this solution 0.5 gram of calcium hydroxide was added, the mixture stirred at room temperature for ninety minutes, then heated to boiling and filtered. The filtrate was reheated to boiling, the pH adjusted to 3.0 and cooled. The brown precipitate which separated was collected, washed with water and dried. There was thus obtained 0.24 gram of oxopterin G whose ultraviolet absorption showed peaks at 258 and 364 mu respectively,

i'tm.

being 855 and respectively.

When hydrolyzed in a like manner 4-amino-6- [para N (diethyl a glutarate)carbamidophenoxylmethylpteridine gives 4 amino 6- [para N (a. glutaric acid) earbamidophenoxylmethylpteridine; 2 methylmercapto 4- amino 6 [para N (diethyl a. glutarate) carbamidophenoxy]methylpteridine gives 2- methylmercapto 4 amino 6 [para N- (a-glutaric acid) carbamidophenoxy] methylpterh dine; 2 thio 4 amino 6 [para N (diethyl a glutarate) carbamidophenoxy] methylpteridine gives2 thio 4 amino 6 [para N (a glutaric acid) carbamidophenoxy]methylpteridine; 2 methyl- 4 amino 6 [para N (diethyl a glutarate) carbamidophenoxylmethylpteridine gives 2 methyl 4 amino 6 [para -N- (a-glutaric acid) carbamidophenoxyl methylpteridine; 6 [para N (diethyl a glutarate)carba'- midophenoxylmethylpteridine gives 6 [para- N (a glutaric acid)carbamidophenoxylmethylpteridine; 2 methyl 4 hydroxy 6 -'[para N (diethyl a glutarate)carbamidophenoxylmethylpteridine gives 2 methyl 4 4 hydroxy 6- [para N (a glutaric acid)carbamidophenoxylmethylpteridine; 2 chloro 6 [para N- (diethyl a. glutarate)carbamidophenoxylmethylpteridine gives 2 chloro 6 [para ,N- (a-glutaric acid) carbamidophenoxy]methylpteridine; 2,4 dihydroxy e [para N (diethyl a glutarate) carbamidophenoxylmethylpteridine gives 2,4 dihydroxy 6[para N (a. glutaric acid) carbamidophenoxy]methylpteridine; 2- ethylmercapto 4 hydroxy 6 [para N (diethyl n. glutarate) carbamidophenoxylmethyl pteridine gives 2 ethylmercapto- '4 hydroxy- 6" [para -N (or glutaric acid). carbamidophenoxylmethylpteridine; 2,4 dimethyl 6- [para N (methyl :1 glutarate)carbamido phenoxylmethylpteridine gives 2,4 dimethyl- 6 [para N (a glutaric acid) carbamidophe noxylmethylpteridine; 2 chloro 4 ethyl 6 [para N (diethyl a. glutarate)carbamidophenoxylmethylpteridine gives 2 chloro 4 ethyl- 6 [para-N -.(a glutaric acid) carbamidophenoxylmethylpteridine;l2 thio 4 hydroxy 6- [para N (diethyl a. glutarate) carbamidophencxylmethylpteridine gives 2 thio 4 hydroxy- 6 [para N (a glutaric acid)carbamidophenoxylmethylpteridine; 4 methyl 6 [para N- (diethyl a glutarate)carbamidophenoxylmethylpteridine gives 4 methyl 6 [para N- (a-glutaric acid) carbamidophenoxylmethylpteridine; 2 amino 6 [para N (diethyl a glutarate)carbamidophenoxylmethylpteridine gives 2 amino 6 [para N (a. glutaric acid) carbamidophenoxy]methylpteridine; 2 amino 4- (p aminostyryl) 6 [para N (diethyl a glutarate) carbamidophenoxy]methylpteridine gives 2 amino 4 (p aminostyryl) 6 [para- N (a glutaric acid)carbamidophenoxylmethylpteridine; 2 amino 4 chloro 6 [para N- (diethyl a. glutarate)carbamidophenoxylmethylpteridine gives 2 amino 4 chloro 6 [para- N,-- (a. glutaric acid) carbamidophenoxylmethylpteridine; and'2 amino 4 methyl 6 [para- N "(diethyl a glutarate)carbamidophenoxylmethylpteridine gives 2 amino 4 methyl 6- [para N (a glutaric' acid) carbamidophenoxylmethylpte'ridine.

When-hydrolyzed in a like manner 2 thio 4- amino 6 [para N (diethyl a glutarate) sulfonamidophenoxy]methylpteridine gives 2 thio- 4 amino 6 [para N (a. glutaric acid) sulfonamidophenoxylmethylpteridine; 2,4 diamino 6 [para N (diethyl a g1utarate)su1- fonamidophenoxy]methylpteridine gives 2,4 diamino 6 [para N (a glutaric acid)sulfonamidophenoxylmethylpteridine; and 2,4 dihydroxy 6 [para N (diethyl a glutarate) sulfonamidophenoxylmethylpteridine gives 2,4 dihydroxy 6 [para N (a. glutaric acid) sulfonamidophenoxyl methylpteridine.

Example 5. N [4-{l(2,4-diamino-6-pyrimido- [4,5 b] pyrazyl)methyllowy}benzoyll L- glutamic acid, also designated as 2,4-diaminc- 6-[para N (a. glutaric acid) carbamidophenom/l methylpteridine A solution of 6.28 grams of diethyl-p-(Z- keto 3,3 diethoxypropoxy benzoyl L glutamate and 2.96 grams of 2,4,5,6-tetraam inopyrimidine bisulfite in a mixture of 20 milliliters of ethanol and 40 milliliters of water was acidified to pH 3.0 with hydrochloric acid and heated to 85-90 degrees centigrade for four hours. A small residue was removed by centrifuging and the pH of the clear hot solution was adjusted to pH 3.2 by the addition of sodium carbonate and the solution cooled. The resulting precipitate of 2,4-diamino-6- [para-N- (a-glutaric acid) carbamidophenoxylmethylpteridine weighed 2.05 grams after collecting, washing with water and drying.

when observed in 0.1 normal sodium hydroxide solution. An additional 1.40 grams was obtained by cooling the filtrate above to degrees centigrade for 24 hours and adjusting the pH to 4.0.

14 Having thus described our "inithtioli' we claim: 1. A member of the group. of fiphenoxymethylpteridines represented by the formula:

3. A 6-phenoxymethylpteridine represented by the formula:

4. A G-phenoxymethylpteridine represented by the formula:

5. A fi-phenoxymethylpteridine represented by the formula:

COOH

6. A 6-phenoxymethylpteridine represented by the formula.

'7. A method for the preparation of fi-phenoxymethylpteridines comprising contacting in solution a 4,5-diaminopyrimidine and a phenoxy-2- keto propionaldehyde acetal and isolating the pteridine thus produced from the reaction mixture.

BL '25. method for the preparation of fi-phenoxyniethylpteridines represented 'by the formula:

and carboxylic acidgroups comprising contacting in solution a compound having the formula:

wherein Y has the values given and R is a, lower alkyl group with a 4,5-diaminopyrimidine having the formula:

wherein Z has the values given and recovering the pteridine thus produced from the solution.

9. A method for the preparation of a compound having the formula:

H:N(N\/N\ l cmo-G-c o o cam comprising contacting in solution ethyl p- (Z-keto- NHz 16 3,3-dieth'oxypropoxy) benzoate and 2,4,5-triamino-G-hydroxypyrimidine and isolating the pteridine thus produced from the reaction mixture.

10. A method for the preparation of a pteridine having the formula:

comprising contacting in solution diethyl p-(2- keto 3,3 diethoxypropoxy) benzoyl L-glutamate and 2,4,5-triamino-6-hydroxypyrimidine and isolating the pteridine thus produced from the reaction mixture.

11. A method for the preparation of a pteridine having the formula: V

N N V HzN l 00011 omwQo-am-dn i i t HaN O O CaHs comprising contacting in solution ethyl-p-(2- keto-3,3-diethoxypropoxy) benzoate and 2,4,51,6-

tetraaminopyrimicline and isolating the pteridine from the reaction mixture.

DAVID I. WEISBLAT. BARNEY J. MAGERLEIN.

No references cited. 

1. A MEMBER OF THE GROUP OF 6-PHENOXYMETHYLPTERIDINES REPRESENTED BY THE FORMULA: 